The present invention relates to transcutaneous, or transdermal, drug delivery systems and, more particularly, to an applicator for use in the transcutaneous iontophoretic delivery of drugs.
A variety of methods for delivering various drugs to patients are in use. For example, many medications are taken orally. The drugs thus ingested are picked up by the blood system in the stomach and intestines and delivered throughout the body.
Another delivery method involves the introduction of the drug directly into the blood stream by injection into a vein of the patient. Such delivery may be made using a syringe for the essentially instantaneous delivery of the drug dosage or a more uniform and prolonged delivery may be achieved by using extended intravenous delivery.
A third delivery method, which is gaining increasingly wide acceptance, involves the transcutaneous transfer of drug, i.e., the transfer of drug into the patient across the skin. In certain circumstances, the transcutaneous delivery of drugs offers significant advantages over other delivery methods. Transcutaneous delivery is particularly advantageous in that it offers the possibility of the continuous and measured delivery of drugs to the body without the complications and inconveniences of intravenous delivery.
Such a measured delivery of drug over a relatively long period of time is particularly desirable in the delivery of drugs which could be harmful if administered in large dosages and for drugs, such as various types of pain relievers, which are most effective when delivered continuously.
A number of transcutaneous drug delivery systems are known. Perhaps the simplest involves placing the drug in contact with the skin and allowing the drug to penetrate the skin by osmosis and/or related spontaneously occurring mass transport phenomena. This technique is commonly used, for example, to administer nitroglycerine.
A more sophisticated transcutaneous drug delivery technique, known as iontophoresis, uses electrical energy to actively cause the drug to penetrate the skin and allows for better control of the rate of drug delivery and its depth of penetration.
Stripped to its bare essentials, iontophoresis involves the application of an electromotive force to drive ionic chemicals, typically drugs, through the skin so that they can be absorbed by the underlying tissues and nearby blood vessels.
An iontophoretic device includes two electrodes. One of the electrodes has in its vicinity the ionic species to be driven into the skin. The other electrode, in close proximity to the first electrode, serves to close the electrical circuit through the body. In use, both electrodes are brought in contact with the skin. An electromotive force is applied to the electrodes which creates an electrical circuit between the two electrodes which runs through the skin and underlying tissues and which drives the ionic drug species away from the first electrode and through the skin.
The iontophoretic transcutaneous delivery of drugs, as presently practiced, is not without its problems. Chief among these is the difficulty in ensuring a relatively uniform low electrical flux across the two electrodes.
It has been widely appreciated that the difficulty in maintaining appropriate electrical flux stems from the difficulty in creating and sustaining good contact between the device and the skin. The skin is normally a rough surface and even when the area onto which the electrodes are to be applied has been shaved of all hair, the remaining surface remains three-dimensional and contains various imperfections and inhomogeneities, such as cut hairs, follicles, cuts, scar tissue, and the like, which militate against the formation of good electrical contact between the applicator and the skin.
Various conducting gels, with and without various flux improving components, have been used to fill the space between the applicator and the skin in order to at least partially overcome some of the difficulties which arises when attempts are made to uniformly contact the essentially flat applicator and the microscopically highly three-dimensional surface of the skin.
Another way of ensuring better contact between the electrodes and the skin is described in U.S. Pat. No. 4,708,716 and involves the use of an applicator which features a plurality of electrodes which are flexibly connected to each other so that the entire applicator is better able to flex and conform itself so as to better echo the macro contours of the skin surface on which the applicator is deployed.
This solution, while useful on the macro scale in conforming the overall shape of the applicator to the shape of the skin surface, is ineffective in overcoming the difficulties caused by imperfections and inhomogeneities in the skin. Some of these features, for example cuts in the skin, present an electrical path which offers significantly lower electrical resistance than the surrounding skin. The lowered resistance brings about the concentration of current in and around the imperfection and, if the local current flux rises sufficiently, can bring about undesirable consequences such as tingling, irritation and even burns. The phenomenon is further aggravated by the fact that the initial concentration of current causes a further decrease in the local resistance and a further increase in the local current. This snowball effects serves to quickly create a `hot spot` which suffers irritation and burns.
Various methods and procedures have been developed or suggested to limit or eliminate such galvanic burns. The general objective is to keep the localized current density, that is, the current per unit area of skin, to below the threshold values at which burns, or unacceptable irritation, can be encountered.
Current density uniformity can be enhanced by avoiding folds, wrinkles and other avoidable inhomogeneities between the applicator and the skin and by using various gel-moistened pads between the electrode and the skin. However, such techniques are ineffective in avoiding irritation and burns caused by the concentration of electrical current as a result of unavoidable, and often undetected, imperfections in the skin, such as microscopic cuts or punctures.
One possible solution is to use an array of electrodes, each of which is connected in parallel to a power source through a dedicated resistor. Each resistor is of a resistance which is relatively large compared to the resistance normally encountered in penetrating the skin. In this way, changes in skin surface resistance cause little effect on the current density.
Transcutaneous drug delivery systems typically employ a current flux of as low as 0.0001 ampere per square centimeter of skin surface, while the electrical resistance of the skin to current flow is on the order of 6 to 9K ohms.
Thus, if a typical power source, such as a 1.5 volt battery, is to be used, the total system resistance per square centimeter of skin surface should be approximately 15 K ohms. Part of this resistance is attributable to the battery resistance and the resistance of various other components of the applicator through which the current travels. The balance of the resistance, which is typically the bulk of the total resistance, is contributed by a dedicated current limiting device, typically a resistor, which is included in the electrical circuit in series with each electrode.
When the skin resistance of a particular location on the skin is significantly lower, as when an open cut is encountered, the local skin resistance drops significantly. However, since the skin resistance constitutes only a small fraction of the local overall resistance, the local overall current increases only slightly and remains below the values which would cause irritation or burns.
The difficulty with such a configuration is that the device described therein is very difficult to build, and thus costly. A related disadvantage is that such a device, being made up of a large number of individual electrodes and resistors, could be unreliable and suffer from an unacceptably short storage and operational life.
There is thus a widely recognized need for, and it would be highly desirable to have, a iontophoretic transcutaneous drug applicator which would have the property of effectively limiting the current flux introduced to the skin to safe levels and which would, at the same time, be very inexpensive to manufacture and highly durable and rugged during storage and use.